CytoCell DiGeorge/ VCFS TUPLE1 and 22q13.3 Deletion Probe Combination

Probe specification

• TUPLE1, 22q11.2, Red
• N85A3, 22q13.3, Green

The TUPLE1 probe is 113kb, labelled in red, and covers most of the TUPLE1 (HIRA) gene. The N85A3 (44kb) probe, labelled in green, is located within 22q13.3 and covers the telomeric end of the SHANK3 gene, allowing for identification of the most distal 22q13.3 deletions. The two unique sequences provide control probes for each other and allow identification of chromosome 22.

Probe information

DiGeorge Syndrome

DiGeorge syndrome¹, and a variety of congenital malformation syndromes including Velocardiofacial syndrome (VCFS)², share the deletion of chromosome 22 at 22q11.2^2,3,4,5.These chromosome 22 deletions are collectively coined CATCH22, a mnemonic that covers the clinical findings of Cardiac abnormality, Abnormal facies, Thymic aplasia, Cleft palate and Hypocalaemia/Hyperthyroidism due to a chromosome 22 deletion.

In addition, around 29% of nonsyndromic patients with isolated conotruncal defects have been shown to have a 22q11.2 microdeletion⁶. The incidence of these anomalies is estimated to be 1:4000 to 1:9700 live births⁷ and the deletion of 22q11.2 therefore represents one of the most common genetic defects.

A region of approximately 2Mb, referred to as the DiGeorge Critical Region (DGCR), is the most commonly deleted region and occurs in up to 90% of patients^5,8,9. Within the DGCR, a minimal critical region of 300-480kb has been described^10,11, containing several genes, including TUPLE1 (HIRA), TBX1, SLC25A1 (CTP) and CLTD.

22q13.3 Deletion Syndrome

The 22q13.3 deletion syndrome presents a recognisable phenotype characterised by hypotonia, delay or absence of expressive speech, global developmental delay, normal to accelerated growth and mild dysmorphic features^12,13.

Some deletions of the terminal region of chromosome 22q are cytogenetically visible. However, a few cases of cryptic deletions have been reported^12,14, suggesting that the actual incidence of 22q telomere deletion may be higher than previously thought.

Several observations of patients with 22q13.3 deletion showed that the SHANK3 (ProSAP2)²⁰ gene, encoding a structural protein of the postsynaptic density of excitation synapses and expressed in the cortex and cerebellum of the brain¹⁵, was disrupted^15,16,17 or deleted¹⁸, making it a candidate causative gene for this syndrome. The deletion varies dramatically in size from 130kb to 9Mb^18,19,20. The use of 22q subtelomeric probes, distal to the ARSA gene, have therefore been recommended for examining all 22q13.3 deletions^20,21.